Pulsatile once-a-day delivery systems for minocycline

Abstract

Pharmaceutical delivery systems containing 7-dimethyl-6-deoxy-6-demethyltetracycline or a non-toxic acid addition salt thereof comprising mixtures or separate administration units of pH sensitive polymer coated spherical granules adapted to release the minocycline in a medium having a pH of in the range of from about 4.0 to about 7.5 and coated or uncoated quick release granules adapted to release minocycline in a medium having a pH of less than about 3.9 or minocycline powder, pH adapted multi-coated compositions and oral dosage unit form liquids, capsules or tablets containing the above are provided. These systems and formulations provide at least minimum therapeutic blood levels of minocycline for at least about 24 hours when administered to a subject only once-a-day. Methods for the preparation of the systems and formulations are provided as well.

We claim: 
     
       1. A pharmaceutical delivery system adapted to provide a therapeutically effective blood concentration level of 7-dimethylamino-6-deoxy-6-demethyltetracycline or a non-toxic acid addition salt thereof for a sustained period of time of up to about twenty-four hours comprising: (I) a multiple delivery vehicle system comprising (A) an initial loading therapeutically effective number of quick release granules which comprise (a) (i) an effective amount of at least one pharmaceutically acceptable excipient; and   (ii) an effective antibacterial amount of 7-dimethylamino-6-deoxy-6-demethyltetracycline or a non-toxic acid addition salt thereof, on or in said quick release granules; and optionally     (b) a substantially uniform polymer coating, on said quick release granules and which is rapidly and substantially completely erodible in a medium having a pH of less than about 3.9; said quick release granules being adapted to release substantially completely said monocycline in a medium having a pH of less than about 3.9;     (A-1) an initial loading therapeutically effective amount of finely divided powder comprising (a) an effective antibacterial amount of 7-dimethylamino-6-deoxy-6-demethyltetracycline or a non-toxic acid addition salt thereof;       (b) an independent effective amount of at least one pharmaceutically acceptable excipient which may be the same as or different than (I)(A)(a)(i); or (A-2) an initial loading therapeutically effective combination of (A) and (A-1); and   (B) a secondary loading therapeutically effective number of pH sensitive polymer coated spherical granules which comprise (a) (i) an independent effective amount of at least one pharmaceutically acceptable excipient which may be the same as or different than (I)(A)(a)(i) or (I)(A-1)(b); and   (ii) an independent effective antibacterial amount of 7-dimethylamino-6-deoxy-6-demethyltetracycline or a non-toxic acid addition salt thereof, on or in said coated spherical granules; and     (b) a substantially uniform pH sensitive polymer coating, the polymer of which may be the same as or different than (I)(A)(b), on said coated spherical granules and which is rapidly and substantially completely erodible in a medium having a pH in the range of from about 4.0 to about 7.5; said coated spherical granules thereby being adapted to release substantially completely said minocycline in a medium having pH in the range of from about 4.0 to about 7.5; or       (ii) one or more multi-coated spheronized pharmaceutical single delivery vehicle compositions comprising: (A) a core comprised of (a) a full or partial secondary loading therapeutically effective antibacterial amount of 7-dimethylamino-6-deoxy-6-demethyltetracycline or a non-toxic acid addition salt thereof; or   (b) at least one granule comprised of (i) an effective amount of at least one pharmaceutically acceptable excipient; and   (ii) a full or a partial secondary loading therapeutically effective antibacterial amount of 7-dimethylamino-6-deoxy-6-demethyltetracycline or a non-toxic acid addition salt thereof, on or in said granule; having applied thereon       (B) a substantially uniform pH sensitive polymer coating which is rapidly and substantially completely erodible in a medium having a pH in the range of from about 4.0 to about 7.5; said core thereby being adapted to release substantially completely said minocycline in a medium having a pH in the range of from about 4.0 to about 7.5; having applied thereon   (C) a quick release coating comprising a full or partial initial loading therapeutically effective antibacterial amount of 7-dimethylamino-6-deoxy-6-demethyltetracycline or a non-toxic acid addition salt thereof; and optionally having applied thereon   (D) (a) a substantially uniform polymer coating, the polymer of which may be the same as or different than (B), and which is rapidly and substantially completely erodible in a medium having a pH of less than about 3.9;   (b) a polymer overcoat, the polymer of which may be the same of different than (B) or (D)(a), or   (c) a combination of (a) and thereon (b) wherein the ratio of quick release granules to pH sensitive polymer granules is 30:70 to 70:30.       
     
     
       2. A pharmaceutical delivery system as defined in claim 1 comprising a mixed blend of (I)(A), (I)(A-1), or (I)(A-2) and (I)(B). 
     
     
       3. A pharmaceutical delivery system as defined in claim 1 comprising separate administration units of initial loading component (I)(A), (I)(A-1), or (I)(A-2) for initial administration and secondary loading component (I)(B) for administration up to about 120 minutes after administration of (I)(A), (I)(A-1) or (I)(A-2). 
     
     
       4. A pharmaceutical delivery system as defined in claim 1 wherein greater than about 70 percent of said minocycline in said initial loading component (I)(A), (I)(A-1), (I)(A-2) or (II)(C) is released from said component in less than about 90 minutes when suspended in a medium of aqueous buffer having a pH of less than about 3.9. 
     
     
       5. A pharmaceutical delivery system as defined in claim 1 wherein greater than about 50 percent of said minocycline in said secondary loading component (I)(B) or single coated core (II)(A) and (B) is released from said component or core in less than about 90 minutes when suspended in a medium of aqueous buffer having a pH in the range of from about 4.0 to about 7.5. 
     
     
       6. A pharmaceutical delivery system as defined in claim 1 wherein from about 5 to about 20 percent of said minocycline in said secondary loading component (I)(B) or single coated core (II)(A) and (B) is released from said secondary loading component or single coated core in about 2 hours when suspended in a medium of simulated gastric fluid having a pH of about 1.2 at about 37° C. 
     
     
       7. A pharmaceutical delivery system as defined in claim 1 wherein from about 20 to about 50 percent of said minocycline in said secondary loading component (I)(B) or single coated core (II)(A) and (B) is released from said secondary loading component or single coated core in about 2 hours when suspended in a medium of simulated gastric fluid having a pH of about 1.2 at about 37° C. 
     
     
       8. A pharmaceutical delivery system as defined in claim 1 wherein said minocycline in said quick release granules (I)(A) comprises from about 10 to about 70 parts by weight and said at least one pharmaceutically acceptable excipient in said quick release comprises from about 90 to about 30 parts by weight based upon 100 parts by weight of said minocycline and said excipient combined and said optional polymer coating on said quick release granules comprises from zero to about 10 parts by weight based upon 100 parts by weight of said minocycline and said excipient combined. 
     
     
       9. A pharmaceutical delivery system as defined in claim 8 wherein said minocycline comprises about 50 parts by weight and said at least one pharmaceutically acceptable excipient comprises about 50 parts by weight based upon 100 parts by weight of said minocycline and said excipient combined. 
     
     
       10. A pharmaceutical delivery system as defined in claim 8 wherein said optional polymer coating comprises from about 1 to about 10 parts by weight based upon 100 parts by weight of said minocycline and said excipient combined. 
     
     
       11. A pharmaceutical delivery system as defined in claim 10 wherein said optional polymer coating comprises about 2 parts by weight based upon 100 parts by weight of said minocycline and said excipient combined. 
     
     
       12. A pharmaceutical delivery system as defined in claim 1 wherein said minocycline in said coated spherical granules (I)(B) or in said core (II)(A) comprises from about 10 to about 80 parts by weight and said at least one pharmaceutically acceptable excipient in said coated spherical granules or said core comprises from about 90 to about 20 parts by weight based upon 100 parts by weight of said minocycline and said excipient combined, and said pH sensitive polymer coating comprises from about 5 to about 35 parts by weight based upon 100 parts by weight of said minocycline and said excipient combined. 
     
     
       13. A pharmaceutical delivery system as defined in claim 12 wherein said pH sensitive polymer coating comprises from about 5 to about 25 parts by weight based upon 100 parts by weight of said minocycline and said excipient combined. 
     
     
       14. A pharmaceutical delivery system as defined in claim 12 wherein said minocycline comprises about 60 parts by weight and said excipient comprises about 40 parts by weight based upon 100 parts of said minocycline and said excipient combined, and said polymer coating comprises from about 5 to about 25 parts by weight based upon 100 parts by weight of said minocycline and said excipient combined. 
     
     
       15. A pharmaceutical delivery system as defined in claim 1 containing from about 25 to about 400 mg of 7-dimethylamino-6-deoxy-6-demethyltetracycline or a non-toxic acid addition salt thereof. 
     
     
       16. A pharmaceutical delivery system as defined in claim 15 containing about 80 to about 280 mg of 7-dimethylamino-6-deoxy-6-demethyltetracycline or a non-toxic acid addition salt thereof. 
     
     
       17. A pharmaceutical delivery system as defined in claim 15 wherein said initial loading (I)(A), (I)(A-1), (I)(A-2) or (II)(C) contains from about 20 to about 200 mg of 7-dimethylamino-6-deoxy-6-dimethyltetracycline or a non-toxic acid addition salt thereof. 
     
     
       18. A pharmaceutical delivery system as defined in claim 15 wherein said pH sensitive polymer coated spherical granules (I)(B) or said core (II)(A) contains from about 20 to about 200 mg of 7-dimethylamino-6-deoxy-6-demethyltetracycline or a non-toxic acid addition salt thereof. 
     
     
       19. A pharmaceutical delivery system as defined in claim 1 wherein said excipient in said quick release granules (I)(A), said powder (I)(A-1), said coated spherical granules (I)(B), said core (II)(A), or a combination thereof, independently, comprises lactose, other mono- or di-saccharides, microcrystalline cellulose, starch, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, crosscarmellose sodium, pregelatinized starch, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, hydroxypropylmethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, microcrystalline cellulose in combination with lactose, microcrystalline cellulose in combination with sodium carboxymethyl cellulose, microcrystalline cellulose in combination with crosscarmellose sodium, or a mixture of any of the foregoing. 
     
     
       20. A pharmaceutical delivery system as defined in claim 19 wherein said excipient in said quick release granules (I)(A) or said core (II)(A) comprises microcrystalline cellulose. 
     
     
       21. A pharmaceutical delivery system as defined in claim 19 wherein said excipient in said coated spherical granules (I)(B) comprises microcrystalline cellulose in combination with crosscarmellose sodium. 
     
     
       22. A pharmaceutical delivery system as defined in claim 1 wherein said pH sensitive polymer coating is selected from (a) methylcellulose   (b) ethylcellulose   (c) hydroxyethyl cellulose   (d) hydroxypropyl cellulose   (e) hydroxypropyl methylcellulose   (f) hydroxypropyl methylcellulose phthalate   (g) cellulose acetate phthalate   (h) hydroxypropyl methylcellulose succinate   (i) a polymer or copolymer of (meth)acrylic acid or an ester thereof   (j) polyvinyl acetate phthalate   (k) a polymer or copolymer of polyvinyl acetate   (l) cellulose acetate   (m) fatty acids and esters thereof   (n) cellulose acetate trimellitate; or   (o) a mixture of any of the foregoing, alone, or in further combination with a plasticizer, a colorant, or a pigment; adapted to dissolve substantially completely in a medium having a pH in the range of from about 4.0 to about 7.5.   
     
     
       23. A pharmaceutical delivery system as defined in claim 22 wherein said polymer coating comprises hydroxypropyl methylcellulose phthalate adapted to dissolve substantially completely in a medium having a pH of about 5.0. 
     
     
       24. A pharmaceutical delivery system as defined in claim 22 wherein said polymer coating comprises a combination of hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose adapted to dissolve substantially completely in a medium having a pH of about 4.0 to about 7.5. 
     
     
       25. A pharmaceutical delivery system as defined in claim 22 wherein said polymer coating comprises hydroxypropyl methylcellulose phthalate adapted to dissolve substantially completely in a medium having a pH of greater than about 5.5. 
     
     
       26. A method of maintaining a therapeutically effective level of 7-dimethylamino-6-deoxy-6-demethyltetracycline or a non-toxic acid addition salt thereof in the blood stream of a warm-blooded mammal for about 24 hours comprising the ingestion of a pharmaceutical delivery system as defined in claim 1. 
     
     
       27. A pharmaceutical delivery system as defined in claim 1 wherein said optional polymer coating on said quick release granules or said optional uniform polymer coating on said multi-coated composition is selected from (a) methylcellulose   (b) ethylcellulose   (c) hydroxyethyl cellulose   (d) hydroxypropyl cellulose   (e) hydroxypropyl methylcellulose   (f) hydroxypropyl methylcellulose phthalate   (g) cellulose acetate phthalate   (h) hydroxypropyl methylcellulose succinate   (i) a polymer or copolymer of (meth)acrylic acid or an ester thereof   (j) polyvinyl acetate phthalate   (k) a polymer or copolymer of polyvinyl acetate   (l) cellulose acetate   (m) fatty acids and esters thereof   (n) cellulose acetate trimellitate; or   (o) a mixture of any of the foregoing, alone, or in further combination with a plasticizer, a colorant, or a pigment; adapted to dissolve substantially completely in a medium having a pH of less than about 3.9.   
     
     
       28. A pharmaceutical delivery system as defined in claim 27 wherein said optional polymer coating comprises hydroxypropyl methylcellulose. 
     
     
       29. A pharmaceutical delivery system as defined in claim 1 wherein said pH sensitive polymer coated spherical granules, said quick release granules, or both, independently, have an average diameter in the range of from about 0.1 to about 2.5 millimeters. 
     
     
       30. A pharmaceutical delivery system as defined in claim 29 wherein said pH sensitive polymer coated spherical granules, said quick release granules, or both, independently, have an average diameter in the range of from about 0.8 to about 1.2 millimeters. 
     
     
       31. A pharmaceutical delivery system as defined in claim 1 wherein said polymer coating on said quick release granules, said coated spherical granules or a combination of the foregoing, independently also, includes a precoating under, an overcoating over or a combination thereof in addition to the pH sensitive polymer coating, of the same or a different polymer. 
     
     
       32. A pharmaceutical delivery system as defined in claim 31 wherein said precoating, overcoating or combination thereof comprises from about 1 to about 10 parts by weight of said pH sensitive polymer coated release spherical granules. 
     
     
       33. A controlled release pharmaceutical composition in oral dosage unit form comprising a hard or a soft shell capsule at least partially filled with a pharmaceutical delivery system as defined in claim 1. 
     
     
       34. An oral dosage unit as defined in claim 33 which also includes a lubricant, a disintegrant, a plasticizer, a colorant, a pigment, a flavoring, an additional medicament, or a combination of any of the foregoing.